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Lactate in sepsis: a sign of feast or famine?. Association of Clinical Biochemists Southwest and Wessex Region SMA Hubble September 2007. _______________________________________ _______________________________________ _______________________________________

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lactate in sepsis a sign of feast or famine

Lactate in sepsis: a sign of feast or famine?

Association of Clinical Biochemists

Southwest and Wessex Region

SMA Hubble

September 2007

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septic shock
Septic Shock

A 70 year lady (Mrs B) is admitted to Intensive Care with severe pneumonia. She is pyrexial, tachypnoeic, tachycardic and hypotensive. These are her blood results:

pH 7.21

paO2 7.1kPa

pCO2 5.8 kPa

HCO3 12 mmol/l

BE -12

Lactate 8 mmol/l

70-80% Mortality

outline
Outline
  • What are the causes of raised lactate in sepsis?
  • Is there any evidence of oxygen debt in resuscitated sepsis?
  • Multi-organ failure…-Is it microvascular or mitochondrial dysfunction?
  • What’s all this about PARP?
  • Can a lactic acidosis be protective?
slide5
“The difficulty lies, not in new ideas, but in escaping the old ones…”

John Maynard Keynes 1933

history and backround of lactate measurement
History and backround of lactate measurement.
  • Initial experiments with animal models of circulatory shock.
  • Lactate as a poor prognostic marker in other shock states.
  • Oxygen delivery DO2 vs Consumption VO2 graphs.
  • Below a critical oxygen delivery point, lactate values rose.
  • Lactate as a sign of oxygen debt in humans.
slide7

Oxygen consumption

Arterial O2 – Venous O2

VO2 mls/min

Critical DO2

Oxygen debt

Lactate

Oxygen delivery

CO x arterial O2 content

DO2 mls/min

300mls/min

history and backround of lactate measurement8
History and backround of lactate measurement.
  • Shoemaker 1980’s
  • “Super-normal” goal oriented approach in high risk surgical patients with high lactate

Shoemaker, Boyd 1993, Wilson 1999.

  • Why “Super-normal” DO2 ?...
a nice theory
A nice theory…

Oxygen consumption

VO2 mls/min

Critical DO2

Oxygen debt

Lactate

Oxygen delivery

DO2 mls/min

300mls/min

the reality
The reality…
  • Increasing oxygen delivery in septic patients does not improve outcome.
  • Too much inotropy kills patients.
  • Increasing oxygen delivery in sepsis does not lower arterial lactate levels.
septic shock is not the same as circulatory shock
Septic shock is not the same as circulatory shock.
  • Failure of supra-normal goal therapy in septic patients…Why?
  • Difficulties demonstrating oxygen debt in sepsis.
  • Poor VO2 rather than DO2 may be the problem
lactate metabolism
Lactate metabolism

CellCytoplasm

Glucose

ADP

Glycolysis

2 ATP

Lactate

Pyruvate

Oxygen

O2 + NADH

Oxidative phosphorylation

36 ATP NAD+CO2+H2O

Mitochondria

evidence for oxygen debt in sepsis
Evidence forOxygen debt in sepsis
  • Global Oxygen debt
    • Delayed or inadequate circulatory resuscitation
    • Increased cellular metabolism.
    • Increased critical oxygen delivery point (cDO2) Rashkin, Haupt, Gilbert
  • Regional oxygen debt
    • Perfusion heterogeneity. Lang, Cryer, Powell
    • Microvascular disturbances, OPL techniques. DeBakker, Ince
    • Covert oxygen debt in vulnerable tissues despite normal DO2 Gutierez, Thio, Vallet.

“Shock lactate”

evidence against oxygen debt in sepsis
Evidence against oxygen debt in sepsis
  • No relationship between SvO2 and lactate

Kraft P et al. Chest 1993, Bakker J et al. Chest 1991

  • Failure of goal directed therapy in non surgical populations Hayes 1994, Gattinoni 1995
  • Lack of evidence of tissue hypoxia in sepsis
    • [31P] MRS Intracellular ATP Astiz, Jepsom, Pasque.
    • [18F] Fluromisonidazole studies Hotchkiss et al.
    • gut mucosal and muscle pO2 Vandermeer and Sair 2001
mechanisms of non hypoxic lactate production in sepsis
Mechanisms of non-hypoxic lactate production in sepsis
  • Accelerated glycolysis
    • Catacholamine mediated
      • Via B2 adrenoreceptors of Na/K -ATP-ase mediated stimulation of glycolysis Liddell 1979, Bungaard 2003, Levy 2007
    • Increased cellular glucose uptake Zeller et al 1991
    • Decreased PDH activity Vary et al 1986

“Stress Lactate”

what s the use of stress lactate
What’s the use of stress lactate?
  • Evidence of lactate as a mobile metabolite for oxiation or recycling allowing ATP provision
  • Signalling molecule involved in cellular redox state and oxidative defence
  • In sepsis, switch away from fatty acid oxidation to glycolysis via lactate reconversion to pyruvate
  • Lactate is a myocardial fuel in shock states
    • ICI-118551 plus DCA worsened mycardial function and bioenergetic status
lactate accumulation due to mitochondrial dysfunction
Lactate accumulation due to mitochondrial dysfunction
  • Evidence of mitochondrial dysfunction
  • Mechanisms
    • Nitric oxide and peroxynitrite mediated inhibition
    • Poly ADP-ribose …the “PARS” hypothesis.
  • Chicken or Egg?
cytopathic hypoxia
Cytopathic Hypoxia

Pyruvate

Lactate

Oxygen

Perioxinitrite

DNA breakage

NO

Oxygen

PARP activation

NADH

tissue lactate production and clearance
Tissue lactate production and clearance
  • Muscle
  • Inflammatory cells
  • Hepatosplanchnic region
  • Lung
  • Brain, myocardium and kidney
clinical implications of elevated lactate
Clinical implications of elevated lactate
  • Prospective data collection
  • 240 consecutive admissions to Derriford ITU

(Jan –June 2003)

  • Lactate at admission and lactate at 24 hours.
  • APACHE II risk of Death score (ROD)
  • ITU and Hospital mortality
  • Wilcoxon rank sum test to look for significant difference in lactate values between survivors and non-survivors
  • Area under ROC curves to test the discrimination of lactate and/or APACHE ROD between survivors and non survivors
results
Results
  • Overall intensive care mortality 29% and hospital mortalities 35%.
  • Lactate on admission and lactate at 24 hours significantly associated with ICU mortality p=0.0002
  • Which is the best discriminating test ?
    • Lactate on admission, lactate at 24 hours, APACHE ROD score, or a combination?
shock and stress lactate
Shock and Stress lactate

Mrs B’s[Lactate] mmol/l

Time (hrs)

future research
Future research
  • Gold standard techniques for the investigation of mitochondrial, cellular and tissue energy status.
  • Resuscitation of the microvascular circulation.
  • Phase 1 trials of PARP inhibitors.
  • Lactate into APACHE data-set.
lactate in sepsis the good the bad and the ugly
Lactate in Sepsis: “The good, the bad and the ugly”..
  • Shock lactate may be “Good” because it is often treatable and helps guide resuscitation.
  • Stress Lactate is probably “Bad” because although it may just reflect hypermetabolism it is more likely a sign of microvascular or mitochondrial distress.
  • Usually there is a mixedpicture…but if lactate is still high at 24 hours, the prognosis is “Ugly”.